| Suppression of SOCS3 increases susceptibility of renal cell carcinoma to interferon-α. | |
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MedLine Citation:
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PMID: 21054677 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Interferon (IFN)-α is one of the most commonly used agents in immunotherapy for patients with advanced stage renal cell carcinoma. However, because of the drug resistance to IFN-α, its benefits are limited. In this study, we examined whether repression of suppressor of cytokine signaling (SOCS) proteins, which are involved in the IFN-induced signaling pathway, can overcome the IFN resistance of renal cell carcinoma. The effect of IFN-α on SOCS3 expression and cell proliferation was examined using IFN-resistant 786-O and IFN-sensitive ACHN cell lines. The effects of SOCS3-targeted siRNA on 786-O xenografts were determined by SOCS3 expression, morphological observation, and tumor volume. The SOCS3 mRNA expression level was significantly increased by IFN-α stimulation in 786-O, but not in ACHN cells. The overexpression of SOCS3 by gene transfection in ACHN cells significantly inhibited the growth-inhibitory effect of IFN-α. Suppression of SOCS3 expression in 786-O cells by siRNA activated the IFN signaling pathway through signal transducer and activator of transcription 1 phosphorylation and recovered sensitivity to IFN-α. An in vivo study indicated that co-administration of SOCS3-targeted siRNA promoted IFN-α-induced cell death and growth suppression in 786-O cell xenograft in nude mice. Morphological observation of the tumors revealed the inhibition of SOCS3-induced apoptosis, invasion of inflammatory cells and fibrosis. SOCS3 could be a key component in the resistance to IFN treatment of renal cell carcinoma. Silencing SOCS3 gene expression could be an effective strategy to enhance the antitumor effect of IFN in human renal cell carcinoma cells. |
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Authors:
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Shintaro Tomita; Kei Ishibashi; Koichi Hashimoto; Takashi Sugino; Tomohiko Yanagida; Nobuhiro Kushida; Keiichi Shishido; Ken Aikawa; Yuka Sato; Tatsuo Suzutani; Osamu Yamaguchi |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-11-05 |
Journal Detail:
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Title: Cancer science Volume: 102 ISSN: 1349-7006 ISO Abbreviation: Cancer Sci. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-16 Completed Date: 2011-01-18 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101168776 Medline TA: Cancer Sci Country: England |
Other Details:
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Languages: eng Pagination: 57-63 Citation Subset: IM |
Copyright Information:
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© 2010 Japanese Cancer Association. |
Affiliation:
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Department of Urology, Fukushima Medical University, Fukushima, Japan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Carcinoma, Renal Cell / drug therapy* Cell Line, Tumor Female Humans Interferon-alpha / therapeutic use* Kidney Neoplasms / drug therapy* Mice Mice, Inbred BALB C Phosphorylation RNA, Messenger / analysis STAT1 Transcription Factor / metabolism STAT3 Transcription Factor / metabolism Suppressor of Cytokine Signaling Proteins / antagonists & inhibitors*, genetics |
| Chemical | |
Reg. No./Substance:
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0/Interferon-alpha; 0/RNA, Messenger; 0/SOCS3 protein, human; 0/STAT1 Transcription Factor; 0/STAT3 Transcription Factor; 0/Suppressor of Cytokine Signaling Proteins |
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